2alpha-lower-alkyl-9alpha-halo-11, 17-dioxygenated-3-keto-4-androstenes



United States Patent 0 3 161 660 za-Lownn-aucYLok-nhLo-l1,17-n1oXYGEN- ATED-fa-KETG--ANDRQSTENES John A. Hogg, Charleston Township, Kalamazoo County,

and William P. Schneider, Kalamazoo Township, Kalamazoo County, Mich assiguors to The Upjohn Compauy, Kalamazoo, Mich 'a corporation of Delaware No Drawing. Filed July 12, 1960, Set. N 42,206

- 6 Claims. (Cl. 260-397.3)

represented by the following sequence of formulae:

cm cm on 0H ice atoms, inclusive, and X is a halogen of atomic weight 34 thru 130.

The process of the instant invention comprises: treating 2:: lower-alkyl-l lfi,17p-dihydroxy-4-androsten-3-one (I) with an acylating agent selected from halides and anhydrides of organic carboxylic acids, preferably hydrocarbon carboiq'lic acids containing from one to eight carbon atoms, inclusive, to obtain the corrmponding 2ozlower-alkyl-l1,8-hydroxy-l7B-acyloxy 4 androsten-3- one (II); treating the thus produced 2a-lower-alkyl 1IB- hydroxy-l7fi-acyloxy-4-androsten-3-one with an .N halo acyl amide in an organic base to give a 2a-lower-alkylllfi-hypohalite-l7fi-acyloxy-4-androsten-3-one and treating this intermediate with sulfur dioxide under anhydrous conditions to obtain the corresponding 2m-lower-alkyl- 17fl-acyloxy-4,9(l l )-androstadien 3 one (Ill); treating the thus produced 2a-lower-alkyl-17fl-acyloxy-4,9(ll)- androstadien-3 one with a hypohalous acid to obtain the corresponding 2a-lower-alkyl-9a-halod lfl-hydroxy 17B- acyloxyA-androstenS-one (IV) wherein the halo is of atomic weight 34 to 130; heating the thus obtained 20:- lower-alky1-9a-halo-1lp-hydroxy-UB-aoyloxy 4 androsten-3-one with an anhydrous alkali metal amtate, such as potassium or sodium acetate to obtain the corresponding 2a-lower-alkyl-9,llB-oxido 171S-acyloxy-4-androsten-3- one (V); treating the thus obtained 2a-lower-alkyl-9J 1poxido-l7,8-acyloxy-4-androsten-3-one with hydrogen fluoride to obtain the corresponding 2a-lower-alkyl-9a-fluorol1fl-hydroxy-17B-acyloxy-4androsten 3 one (VI) and oxidizing the thus produced 2u-lower-alkyl-9a -fiuoro- 11 B-hydroxy-l 7fi-acyloxy 4androsten-3 one with chromic wherein the lower-alkyl group contains from one to eight carbon atoms, inclusive, R is selected from the group consisting of hydrogen and acyl in which the acyl radical is of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eight carbon 4androste'ne-3,l1'-dione (VII); hydrolyzing with a base 2a-lower-alkyl-9z-fluoro-17p acyloxy -'4 androstene-B, ll-dione to give the 2a-lower-alkyl-9a-fluorol7flhydroxy-tandrostene-Lll-dione and oxidizing Zen-loweralkyl-9az-tiuoro-17p-hydroxy-4-androstone-3,1l-dione with chromic acid to'give 2hr-lower-alkyl-9a-fluoro-4-androstone-3,11,17-trione (VH1).

The starting materials of Formula I of the flow-sheet in column 1 are prepared in the manner disclosed in abandoned parent application Serial No.

namely, by reduction of a Za-lower-alkyl-llfl-hydroxy-4-androstene3,l7-dione, preferably with an alkali metal borohydride, to produce a mixture of a corresponding 20: lower-alkyl-l118,17B-diliydroxy-4-androsten-3-one (I) and a corresponding 2a-lower-alkyl-3BJlp,17p-trihydroxy-4-androstene; oxidation of this mixture, preferably with manganese dioxide, yields a corresponding Zea-lowerallcyl 1113,1713- dihydroxy 4 androsten 3 one (I),

exclusively. V The instantly produced compounds, 2a-lower-alkyl-9ahalo-1 lp-hydroxy- 4 androstene-3,l7-dione, Zen-lower alkyl-Qwhalo-l lp-hydroxytestosterones, 2m-lower alkyl-9ahalo-1 l-ketotestosterones, 2m-lower-alkyl-9a-halo-adrenm sterone, and the esters of these compounds are important physiologically active compounds, having strong androgenic, anabolic, antiestrogenic, and adrenoeortical activity and are useful in formulations in place of cortisone. The compounds in addition have anti-inflammatory, antipituitary, and anesthetic activity. 2a-lower-alkyl-9m-halo-adrenosterone, can be reacted with a methyl magnesium halide to give the corresponding 2-lower-alkyl-9m-halol 7a-methyl- 17B-hydr0Xy-4-androstene-3, l l-dione.

In order to obtain the 9a-halo compounds of this invention a 2m lower-alkyl-llfi-hydroxy-l7B-acyloxy-4-androstene-3-one is dehydrated to the corresponding 2vz-lOW- er-alkyl-17 B-acyloXy-3,9 (l l )-andr0stadiene-30ne. Dehydrating agents suitable are, for example, phosphorous oxychloride, hydrochloric acid, or sulfuric acid in acetic acid or pyrolysis as shown by US. Patents 2,640,838 and 2,640,839. In the preferred embodiment of the present invention the dehydration is eliected by reacting the 115- hydroxy compound with N-haloamide or N-halcirnide in an organic base and treating the thus produced intermediate ll-hypohaiite with dry sulfur dioxide. As reagents for the production of an ll-hypohalite, N-haloamide or N-baloimide wherein the halogen has an atomic weight from 34 to 130, inclusive, preferably chlorine or bromine, are used. Examples of such compounds are N-chloroacetamide, N-bromoacetamide, N-chlorosuccinimide, N- bromosuccinimide, N-iodosuccinimide, 3-brorno-5,5-di methylhydantoin and l,3-dibromo-5,5-dirnethylhydantoin. Ordinarily an amount in excess of a molar equivalent, calculated on the starting llfi-hydroxy steroid, is employed. The bases employed in the production of the llhypohalite are tertiary amines with the amino nitrogen as a member of an aromatic ring, for example, the pyridines, that is, pyridine, alkyl pyridines, piccoline, lutidine, bollidine, conyrine, parvuline, or the like or lower fatty amides, such as formamide, mcthylformamide and dimethylformaniide. The base is preferably employed in a large molar excess, calculated on the starting 1l,8-hy droxy steroid, for example, ten molar equivalents, and is preferably the sole reaction solvent. The reaction to produce an ll-hypohalite is generally conducted under anhydrous conditions preferably containing less than 0.1 molar equivalent of water calculated per mole of steroid. Large proportions of water decrease the yield. The temperature of the reaction is between minus forty and plus seventy degrees .centigrade, the lower limit being determined by the solubility of the reaction and solvents and the upper limit being determined by the amount of side reaction which normally accompanies the reaction involving halo compounds at higher temperatures. Ordinarily, room temperature (twenty to thirty degrees centigrade) is preferred for convenience and consistently high yields of the desired product which are obtained at this temperature. A reaction period between five minutes to three hours is usually employed. At a higher temperatum, above thirty degrees centigrade, short reaction times are suflicient to produce completeness of the reaction.

'Ihe thus produced 2a-lower-alkyl-l lfi-hydroxy- 17fi-acyloxy-4-androstcn-3-one llp-hypohalite is then treated with anhydrous sulfur dioxide in the presence of an organic base as described hereinbefore. The anhydrous sulfur dioxide canbe in the form of gaseous, or liquid sulfur dioxide. The reaction temperature ranges substantially within about minus forty and about plus seventy degrees Centigrade and preferably room temperature (twenty to thirty degrees centigraclc) The thus obtained product, a 20:. lower-alkyl 1 1,8 acyloxy-4,9(l1)-androstadien-3- one is isolated by conventional means such as extraction from the reaction mixture after the reaction mixture has been poured into excess of water. The thus obtained reaction mixture by pouring the reaction mixture into exextracts are conveniently washed, dried and thereupon evaporatcd to give crude 2a-lower-alkyl-l7fl-acyloxytional means such as recrystallization or chromatography,

as deemed necessary. The thus obtained 2a-lower-alkyl- IJB-acyloxy 4,9(11) androstadien-3-one is converted to Z0: lower-alkyl-9a-halo 11 9 hydroxy-l 7-acyloxy-4-an drosten-3-one thereof by adding a hypohalous acid such as hypocblorous or hypobromous acid. The hypohalous acid can be addedjn aqueous alcoholic solution, but it usually produced in situ by reacting an N-halo acid amide or an N-halo acid imide with an acid to liber te hypchalous acid. In the preferred'embodiment of the invention, a 2m lower-alkyl-l7B-acyloxy-4,9( l l)-androstadiene-3-one is dissolved in an organic solvent such as-methylene chlo ride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like and reacted at room temperature with the hypobromous, hypochlorous, or hypoiodous acid releasing agent. Such hypohalous acid releasing agents include the N-bromoacetamide, the N-chloroacetamide, the N-brornosuccinimide, the N-iozlosuccinimide. or the like in the presence of Water and an acid such as perchloric acid,

dilute sulfuric acid, or the like. The reaction is usually carried out at room temperature between fifteen to thirty degrees ccntigrade, however, lower or higher temperatures are operative for the process. The hypohalous acid releasing agent is generally used in equirnolar or slightly increased proportions, for example, 25 percent increase over the theoretical. A large excess of the hypohalous acid releasing agent while operative is undesirable since the excess hypohalous acid has a tendency to act on other positions of the molecule. The reaction period is rather short and may vary between four to'five minutes to one hour. At the end of the reaction time, excess of hypohalous acid is destroyed by the addition of sodium sulfite or other sulfites or hydrosulfites. The thusmro duced product, a 2m-lower-alkyl-9a-halo-l lfi-hydroxyl'ifl-scyloxy-4-androstem3-one, wherein halo is of atomic weight between 34 and 130, is isolated from the reaction mixture by adding excess of water and extracting the compound with organic solvents or by recovering the precipitated compound through filtration. The crude product thus obtained may be recrystallized from acetone and Skellysolve B hexane hydrocarbons to give pure Zen-loweralkyl 9a halo-1lfi-hydroxy17e-acyloxy-4-androstem3- ones, respectively, the corresponding esters thereof.

The l7p-ester thus obtained is hydrolyzed to give the free diol, 2a-lower-alkyl 9a halo-l 1B,17fi-dihydroxy-4- androsten-3-one, which can be recsterified with anhydrides or halides of organic carboxylic acids, preferably hydrocarbon carboxylic acids, to give other monoesters.

oxidizing the l7-ester of a 2a-lower-alkyl-9whalo-llfi, l7fl-dihydroxy-4-androsten-3-one with chromic acid pro duces the corresponding 2a-lowcr-alkyl 9a-halo-l7B-acyloxy-4-androstene-3,1l-dioue which by hydrolysis, as shown before, gives the free diol, 2a-lower-alkyl-9a-hal0- l7fi-hydroxy-4-androstene-3Jl-dionc.

Further oxidation of 2a-lower-alkyl-9a-halo-l'lfl-hydroxy-4-androstcne-3,1l-dione produces the corresponding 2a-lower-alkyl-9a-halo-4-androstone-3,1lJZ-trione (2-.

lower-alkylr9a-halo-adrenosteronc I In order to obtain the most active 9a-fluoro-compounds, the 9,11p-oxido intermediates of the before mentioned compounds, 21 lower-alkyl-Qpd lfl-oxido-l'lB-acylox'ylr androsten-B-one are prepared. In carrying out this read-Y tion, a 2a-lower-alkyl-9-halo-l lp-hydroxy-flfl-acyloxy- 4-androsten-3-one is heated in solution with anhydrous sodium or potassium acetate. Solvents such as methanol, ethanol, acetone, tertiary butyl alcohol, or the like may be used. The reaction time is between one-half hour and 24 hours with a period between three and twelve hours generally sufficient. The thus obtained 2m-lower-alkyl-9fi,l 1B- oxido-l7fi-acyloxy-4-androsten-3-one is isolated from the cess water and extracting with methylene chloride or other water-immiscible solvents such as ether, Slrellysolve B hexancs, pentanes, benzene, ethyl acetate, chloroform, carbon tetrachloride, or thelike. Evaporation of the solvent of the extracts produces crude lm-lower-alkyl-9fi, w

l lB-oxido-17fi-acetoxy-4-androsten-3 -one.

The thus obtained 2a-lower-alkyl-9BJ lp-oxido-Upacyloxy-4-androsten-3-one is thereupon reacted with hydrofiuoric acid, usually in 48 percent concentration. As solvents for this reaction, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, or the like, are useful, with methylene chloride preferred. Sometimes strong acid catalysts are employed such as perchlozic acid, toluenesulfonic acid, sulfuric acid, or the like. The reaction is carried out at room temperature preferably under stirring. The reaction period is from one to 24 hours with a periodfrom one to twelve hours preferred. After the reaction is terminated, the mixture is poured into water and neutralized with a dilute base such as sodium bicarbonate, potassium bicarbonate, or the like. Excess of strong bases can also be used, however, hydrolysis of ester groups is then expected. The reaction mixture is thereafter extracted with a water-immiscible solvent such as methylene chloride and the extracts evaporated to give the crude 2a-lower-alkyl 90c fluoro 115 hydroxy-l7B- acyloxyl-androsten-3-one. The thus obtained crude compounds may be purified through recrystallization or chromatography as deemed necessary.

The 2u-lower-alkyl-9a-fluoro-1lfi-hydroxy-NB-acyloxy- 4-androstene-3-one obtained by this process can be hydrolyzed with a base such as sodium hydroxide, potassium hydroxide, sodium or potassium carbonate to give the diol, 2oz lower-alkyl-9a-fluoro-1lB,l7B-dihydroxy-4-androsten- 3-one.

Oxidation of the 2a-lower-alkyl-9ot-fluoro-llfl-hydroxy- 17/3-acyloxy-4-androsten-3-one with chromic acid in acidic acid produces the corresponding 2a-lower-alkyl-9a-fiuorol7o-acyloxy-4-androstene-3,1l-dione which can be hydro lyzed with sodium bicarbonate in ethanol in a nitrogen atmosphere to give the free alcohol, Za-IoWer-alKyl-Safluoro-l7fi-hydroxy-4-androstene-3, 1 l-dione.

Oxidation of 2a-lower-alkyl-9a-fluoro-l7p-hydroxy-4- androstene-3,ll-dione with chromic acid in acetic acid produces the corresponding 2tX-lOWBI-HlkYl-90t-fillDIG-4- androstene-3,ll,l7-trione (2a-lower-alkyl-9e-fiuoro adre nosterone).

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

EXAMPLE 1 2 oc-M ethyl-1 1 s-Hydroxy-17fi-Acetoxy-4-A na'rosten- 3-0ne the thus obtained precipitate collected on filter paper and recrystallized to give pure Za-methyl-Ilfi-hydroxy-Nfiacetoxy-4-androsten-3-one.

EXAMPLE 2 2u-Ethyl-1lp3-Hydr0xy-1 7 p-Benzoyloxyl-A ndrosten- In the same manner as given in Example 1, 2u-ethyl- 1113,17,8-dihydroxy-4-androsten-3-one, dissolved in pyridine, was treated with benzoyl chloride to give hit-ethyll lfi-hydroxy-l7fi-benzoyloxy-4-androsten-3-one.

EXAMPLE 3 In the same manner as given in Examples 1 and 2, reacting in pyridine solution:

(a) Zwmethyld1,9,17 3-dihydroxy-4-androsten 3 one with propionic anhydride yielded 2m-methyl-1l l3-hydroxy- 17fi-propionyloxy-4-androsten-3-one.

(b) Za-methyi-I113,17,3-dihydroxy-4-androsten 3 one with butyric anhydride yielded 2a-metl1yl-ll 3-hydroxy- 17fi-butyryloxy-4-androsten-B-one.

(c) Zu-methyl-I 113,17fi-dihydroxy-4-androsten 3 one with valeric anhydride yielded Za-rnethyl-llB-hydroxy- 17fi-valeryloxy-4-androsten-3-one.

(d) Zcx-methyl-I1,8,17 3-dihydroxy-4-androsten 3 one with fi-cyclopentylpropionyl bromide yielded Ze-methyL i1 3 hydroxy 17B (B-cyclopentylpropionyloxy) -.4- androsten-S-on'e.

(e) 2a-methyl-11,8,l7fl-dihydroxy-4-androsten 3 one with Z-furoyl chloride yielded Za-rnethyl-llfl-hydroxy- 17B-(Z-furoyloxy)-4-androsten-3-one.

(f) 2a-ethyl-l 1 {3, l7B-dihydroxy-4-androsten-3-one 'with propionic anhydride yielded Za-ethyl-l 15-hydroxy-l7 8- propionyloxy-4-androsten-3-one.

(g) Za-propyl-l1{3,l75-dihydroxy-4-androsten 3 one with hexanoyl bromide yielded 2m-propyl-1l5-hydroxyl7 8-hexanoyloxy-4-androsten-3-one.

(h) Zrx-blliYl-llfl, l7 3-dihydroxy-4-androsten 3 one 6 with toluyl bromide yielded 2u-butyl-llB-hydroxy-Ufitoluyloxyt-androsten-3-one.

(i) 2or-hexyl-l1t ,l7,8-dihydroxy-4-androsten-3-one with phenylacetyl bromide yielded 2a-hexyl-llfl-hydroxy-l7fiphenylacetoxy-4-androsten-3-one.

(i) Ze-octyl-l1,8,17B-dihydroxy-4-androsten-3-one with phenylpropionyl chloride yielded Za-OClYl-l lfi-hydroxy- 1718-phenylpropionyloxy-4-androsten-3-one.

(k) 20:: benzyl 11B,l7,6-dihydroxy-4-androsten-3-one with octanoyl bromide yielded 2a-benzyl-1lfi-hydroxy- 175-octanoyloxy-4-androsten-3-one.

In the same manner as given in Examples 1 and 3, other lor-lower-alkyl-llfi-hydroxy-l7fi-acyloxy-4-androsten-3-ones are prepared by reacting the corresponding 20c lower alkyl 1l B,l7,6-dihydroxy-4-androsten-3-ones with a halide or anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to eigth carbon atoms. Representative 20:- lower-aliryl-llfi-hydroxy-l7B-acyloxy-4-androsten-3 ones include those wherein the lower-alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, phenyl, benzyl, or the like, and wherein the acyloxy group is formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, henzoyloxy acid, succinyloxy, acid tartaryloxy, chloroacetoxy, iodoacetoxy, fluoroacetoxy, bromoacetoxy, trichloroacetoxy, trifiuoroacetoxy, chlorobenzoyloxy, phenylacetoxy, phenylpropionyloxy, meta-, para-, and also nitro-benzoyloxy, or the like.

' EXAMPLE 4 Zrx-Methyl1.7;8-Acet0ay-4,9 (1 Z -A ndrostadiene-3-one The 2rx-methyl-l 1 fi-hydroxy- 1 7fi-acetoxy-4-androsten- 3-one obtained in Example 1, was dissolved in pyridine. Thereto was added one molar equivalent of N-bromoacetamide under continuous stirring. After thirty minutes of stirring anhydrous sulfur dioxide was passed through the flask until a negative test was obtained with starch iodide paper. The reaction mixture was thereupon diluted with water and extracted with methylene chloride. The methylene chloride extracts were evaporated to give ZwIIlfithYl-17B-21Ct0XY-4,9(ll)- androstadien-3-one.

EXAMPLE 5 In the same manner as shown in Example 4, treating Za-ethyl-ILB-hydroxy-l7fl-acetoxy-4-androsten-3-one with N-chlorosuccinimide in pyridine solution and thereafter with anhydrous sulfur dioxide gave 2u-ethyl-l7fi-acetoxy- 4,9 l l )-androstadien-3-one.

EXAMPLE 6 In the same manner as given in Example 4, reacting in pyridine solution: p

(a) Zrx-rnethyI-llB-hydroxy-17p-propionyloxy-4-androsten-B-one with N-bromosuccinimide and thereafter with anhydrous sulfur dioxide yielded 2a-methyl-1713-propionyloxy-4,9 (l l -androstadien-3-one.

(b) Za-methyl-l 1B-hydroxy-UB-butyryloxy 4 androsten-S-one with N-brornosuccinimide and thereafter with anhydrous sulfur dioxide yielded 2e-rnethyl-l7fl-butyryloxy-4,9 1 1 -androstadien-3 -one.

(a) Ze-methyI-l lfi-hydroxy-17,8-valeryloxy 4 androsten-3-one with N-bromosuccinirnide and thereafter with anhydrous sulfur dioxide yielded 2or-methyl-17fi-valeryloxy-4,9(1l)-androstadien-3one.

(d) Zea-mBthYl-l 1B-hydroxy-l7e-( B-cyclopentyl propionyloxy)-4-androsten3one with N-bromosuccinimide and thereafter with anhydrous sulfur dioxide yielded Za-methyI-17B-(fi-cyclopentylpropionyloxy)-4,9 l 1) an drostadien-3-one.

sten-3-one with N-brornosuccinimide and thereafter with anhydrous sulfur dioxide yielded 2ot methyl-17fl-(22-furoyloxy)-4,9(11 )-androstadien-3-one.

A (f) 2 r-ethyl-l1/3-hydroxy-17/3-propionyloxy 4 androsten-3-0ne with N-broniosuccinimide and thereafter with anhydrous sulfur dioxide yielded 2ot-ethyl-l7/3-propionyb oxy-4,9(1l)-androstadien-3-one.

(g) 2oa-propyl llfi-hydroxy-17fl-hexanoyloxy-4-androsten-3-one with N-bromosuccinimide and thereafter with anhydrous sulfur dioxide yielded 2a-pr0pyl-l7,8hexanoylxy-4,9(11)-androstadien-3-one.

one i with N-bromosuccinimide and thereafter with anhydrous sulfur dioxide yielded Zoz-butyl-17B-toluyloxy-4,9

(11 )-androstadien-3-one.

(i) 2qc-hexyl-llfi-hydroxy-l7fi-phenylacetoxy-4 androste'n-3-one with N-brornosuccinirnide and thereafter with anhydrous. sulfur dioxide yielded 2et-hexyl-17fl-phenyl: acetoxy-4,9 11 )-androstadien-3-one. V (j) 2c; octyl llfi-hydroxy-l7,8-phenylpropionyloxy-4- andr0sten-3-0ne with N brornosuccininiide and thereafter with anhydrous sulfur dioxide yielded 2'a-octy1-17B- phenylpropionyloxy-4,9 1 1 )-androstadien-3 one.

(k) Za-benzyl-l1,B-hydroxy-17,8-octanoyloxy-4 -andro'- sten-3-one with N-bromosuccinimide and thereafter with V anhydrous sulfur dioxide yielded 2a-benzyl-l7fl-octaoyloxy-4,9(11 )-androstadien-3-one.

EXAMPLE 7 V Za-Me ZhyI-Qu-BromO-J lfi-Hydroxy-UdA ce t o xyl- Androsteri-S-One i The Za-methyI-17,8-acetoxy-4,9 ll androstadiene -3- one produced in Example 4, was dissolved in fifteen rnilliliters of methylene chloride and milliliters of tertiary butyl alcohol. To this solution was added a solution of 1.25 milliliters of seventy percent perchloric acid in 8.5 milliliters of water and thereto was added 0.2 gram of N-bromoacetamide, dissolved in five milliliters of tertiary butyl alcohol. After stirring the reaction mixture for a period of fifteen minutes at room temperature (22 to 25 degrees centigrade), 0.25 gram of sodium sulfite in twelve milliliters of water was added. The reaction mixture was thereupon concentrated to about six milliliters of volume and'thereto Was added five milliliters of water; The thus produced precipitate was collected on filter paper and recrystallized to .yield 2u -methyl-9oc-bron1o-l1fihydroXy-l7/3-acetoxy-4'androsten-3-one. I I

In the same manner as shown-in Example 7; Za-ethyl- 17B-acetoxy-l,9(1l)-androstadien-3-one was treated in tertiary bu tyl alcohol and methylene chloride with a solu tion of N-chloroacetamide; dissolved in tertiary butyl alcohol in the present of aqueous 'perchloric" acidto give 2cc-6tl1yl-9a-Cl11010-l IB-hydroxy-Ufi-acetoxy 4 androsteri-S-oneL'. a

EXAMPLE y In the same manner as given in Example 7 reacting: (a) Zd-methyl-17fl-propionyloxy-4,9 l l )-androstadien- 3-one with N-bromoacetaneide and perchloricfacid in solu- -1 1 fi-hydroxyf ljfi-propionyloxy-4-adrosten-3one. Y

(b 2 a-rnethyl- 17 fl-butyryloxy-4,9 (1 l )-androstadien-3-s one with N-iodosuccinixnide and perchl'oric acid soluoxy- 4-androsten-3-one.

(c) Za-methyl-l7fi valeryloxy-4i9 1 androstadien-Si one with N-chlorosuccinimide and perchloric acid in soluryloxy-4-androsten 3-one.

tion yielded 2et-ethyl-9a-brorno-11fi hydroxy 17,6-pr0 pionyloxyl-androsten-fl-one.

(g) 2oz-propyl-17,8-hexanopyloxy-4,9 1 1 -androstadien- 3-one with N-brornoacetamide and perchloric acid in solu tion yielded 2oc-propyl-9or-bromo-l1,6-hydroxy-17fi-l1exanoyloxy-4-androsten-3-one.

(h) Za-butyll7fl-toluyloxy-4,9 l 1 -androstadien-3-one with N-bromoacetarnidei and perchloric acid' in solution yielded 7 2o -butyl-9oa-brorno-l lfi-hydroxy-17,8-toluyloxy-4- androsten-3-one.

' i ZtX-hBXYl- 17 ,B-phenylacetoxy-4Q 1 1 -androstadien- 3-one with N-bromoacetarnide and perchloric acid in solution yielded Zfi-h6XYl-9 a-brorno-l l B-hydroxy-17 ,B-phenylacetoxy;4-androsten-3-one. a

(j) Za-octyl- 17 {3-pheny1propionyloxy-4,9 1 1 -androstadien-3-one with N-brornoacetarnide and perchloric acid in solution yielded Za-octyl brorno 1 11B hydroxy-l7fiphenylpropion'yloxyl-androsten-3-one.

k) Zm-benZ'yl-17fl:octanoyloxy-4,9( 1 1)-androstadien-3- one with N-brornoacetamide and perchloric acid in solution yielded 2ot-benzyl-9oc-brorno-1lfl-hydroxy-flfi-octanoyloxy-4-androsten-3-one. I a

In the same manner as given in Examples-7', 8 and 9, other 2m-lOWI-aikY1-9oz-hal0 l1/3-hydroxyd7B-acyloxy- 4-androsten-3 ones are prepared by'reacting the corresponding 2ut-lower-alkyl- 17 ,B-acyloxy-4,9 1 l -'androstadien-3-one with a N-haloacylamide in aqueous acidified solution. In this manner lower-alkyl-9ot-halo-1lfi-hydroxy- 17(3-acyloxy+4;androsten-3-ones are prepared wherein the 2e-loWer-alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, .benzyl or phenyl, wherein the halo is 'brorno, chloro, and iodo, with bromo preferred, and wherein the acyloxy group is of an organic carboxylic acid,'preferably of a hydrocarbon carboxylic acid containing from one to-eight carbon atoms, illustratively acyloxy groups as described in Example 3.

EXAMPLE 10 2a-Methyl-9u-Brom0-11,6,17ii-Dihytlfoxy-4-AndrOsIen-S- A solution was prepared containing one gram of Zeah1ethyl-9a-hromo-l1B-hydroxy-17B1acetoxy-4 androsten- 3-one in fifty'milliliters of methanol.

was added one milliliter of sulfuric acid dissolved in five To this solution inilliliters of water. Thethus obtained mixture Was allowed to stand for a period of 48 hours and thereupon poured into milliliters office water. The reaction,

rnixturewas then extracted'with three 25 -milliliter portions of methylene chloride,'the methylene, chloride solu 7 tion was dried, evaporated and the residue recrystallized v 3 from Skellysolve B hexane and acetone to give Zia-methyl- 9ct-brom0-11e;l-7,B-dihy :lroxy-4-androsten 3one 9pc-chloro- 1lfi-hydroxy-l7fieacetoxy-4-androsten-3-one was hydrolyzed in an'acid medium using tertiary butyl alcohol as solyent and diluteaqueou's sulfuric acid as the acid catalyst ;to give Zea-.teiilYl-QofllhlOIQ-llflfljfi dihydlOXyx4-an drosten-3-one.

In the same manner as shown inExarnple 10, Zea -ethyl I androsten-S-ones comprise those wherein the lower-alkyl group is methyl, ethyl, propyl, isopropyi, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, phenyl and benzyl, or the like, and wherein the acyloxy group is described and defined as in Example 3.

EXAMPLE 19 Za-MethyZ-Qu-FZMOm-JJ 6,1 7,8-Dihydrxy-4- A ndr0stene-3-One 17fl-acetoxy-4-androsten-3-one was refluxed with 025 gram of potassium carbonate, dissolved in 25 milliliters of methanol. The mixture after one hour of refluxing was poured into 100 milliliters of ice water and the thus obtained reaction mixture was extracted with methylene chloride. The methylene chloride layers were evaporated after drying over anhydrous sodium carbonate and the resulting residue was recrystallized from acetone Skellysolve B hexanes to give pure 2oa-methyl-9a-fluoro-1l/3, l7,8-dihydroxy-4-androsten-B-one.

EXAMPLE 20 2et-Ethyl- 9a-Fluoro-l15,175-Dihydroxy-4- Androsten-S-One In the same manner given in Example 19, hydrolyzing 20c ethyl-9a-fluoro-llfi-hydroxy-lm acetoxy-4-androsten-3-one with potassium carbonate in ethanol produced 204 -'e thyl-9er-fluoro-l1,6,l7,8 dihydroxy-4-androsten-3- one. P

EXAMPLE 21 EXAMPLE 22 Zu-MeZhyI-Qu-BrOmO-I 7,8-A cet0xy-4- Andros tene-iII-Dione One gram of 2ott-methyl-9a-bromo-llfl-hydroxy-UfiacetoxYA-androsten-S-0ne, prepared as in Example 7, dissolved in twenty milliliters of acetic acid and one milliliter of water, was treated with one half gram of sodium dichromate dihydrate at room temperature for a period of two hours. Thereafter the reaction mixture was poured into 100 milliliters of water and neutralized by the addition of dilute sodium hydroxide. The mixture was thereupon extracted with methylene chloride, the methylene chloride extract was dried and evaporated and the thus resulting residue was recrystallized from ethyl acetateto give 2a-methyl-9m-bromo-l7/3-acetoxy-4-androsten 3,11-

The thus obtained 2a-methyl-9a-bromo-17,8-acetox -4- androsten-3,ll-dione was hydrolyzed as shown in Examerase dione of Example \22, with chromic anhydride in acetic acid solution results in 2a-methyl-Qa-bromo-4-androstene- 3,11,17-trione (2a-methy1-9a-bromoadrenosterone).

Oxidizing 2a-lower-alkyl-9u-halo 11B hydroxy-17fiacyloxy steroids with chromic acid in acetic acid wherein the alkyl group is'methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, or the like, and wherein halo is selected from chloro, bromo, and iodo and acyloxy is defined and described as before in Example 3, the corresponding 2a-lower-alkyl-9a-halo-17fi-acyloxy 4 androstene-3,ll-diones are obtained. Hydrolysis of such 20clower alkyl-9a-halo-l7fl-acyloxy-4-androstene 3,11- diones give the corresponding 2u-lower-alkyl-9a-halo-17phydroxy-4-androstene-3,ll-diones which are oxidizable in acetic acid with chromic anhydride to the corresponding 2-lower-alkyl-9a-haloadrenosterones (Zoc-lOWGI-alky1-9oahalo-4-androstene-3,11,17-triones).

EXAMPLE 24 In the same manner as shown in Example 2 2, oxidaple 19 in methanol with potassium carbonate to give 2 5-"- 2o: methyl-9a-bromo-l'7fl-hydroxy-4-androstene 3,11-

androsten-3-one with sodium dichromate in acetic acid solution produced 2a-methyl-9a-fiuoro-l7 3-acetoxy-4-androstene-3,l1-dione.

Hydrolysis of 2or-methyl-9a-fluoro-17B-acetoxy-4-andro- 2a-Melhyl-9a-Fluoro-4-A ndr0stene-3,1 1,1 7-Tri0ne In the manner shown in Example 22, oxidizing 2amethyl 9oz fluoro-17fl-hydroxy-4-androstene-3,1l-dione with chromic anhydride in acetic acid in the presence of water produced 2a-methyl-9a-fiuOIO-4-21I1dl08t6116-3,11,17- trione 2a-rnethyl-9wiluoroadrenosterone) In the same manner as given in Example 25 oxidizing 2a lower-alkyl-9vt-fiuoro-1 1B,17fi-dihydroxy-4-androsten- 3-ones produces the corresponding 2a-lower -alkyl-9ufluoroadrenosterones wherein the alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, phenyl, benzyl, or the like. I

We claim:

1. 2a methyl-9a-fiuoro-17fl-acetoxy-4-androstene-3,l ldione. t

3. A process for the production of a 2u-lower-alkyl-9ufluoro-4-androsten-3,11,17-trione which comprises the steps: reducing a 2a-lower-alkyl-llfi-hydroxy-4 androstene-3,l7-dione wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive, with an alkali borohydride to reduce the l7-keto group and oxidizing the resulting mixture with manganese dioxide to obtain 20:- lower-alkyl-l l 5,17p-dilrydroxyl-androsten-3-one; esterifying the thus obtained 2rx-lower-alkyl-llfi,l7p diliydroxy- 4-androstens3-one with an acylating agent selected from halides and anhydrides of organic carboxylic acids containing fromlone to eight carbonatoms, inclusive, to obtain the corresponding 2a-lower-alkyl-l1B hydroxy-17a acyloxy-4-androsten-3-one; treating the thus produced 20:- lower alkyl-llfi-hydroxy-l7a-acyloxy-4-androsten-3:one with an Nhalo-acylamide wherein the I halogen is of atomic weight 34' to 130, inclusive, in an organic base under anhydrous conditions and treating thethus produced intermediate, llfihypohalite, with sulfur dioxide under anhydrous conditions to obtain the corresponding 2alower alkyl 17p acyloxy-4-,9(l1)-androstadien-3-one; treating the thus produced 2a-lower-alkyl-17,8-acyloxy- 4,9 1 1 )-andros'tadien-3-one with a hypohalous acid wherein the halogen is of atomic weight from 33 to 130, in-' elusive, to obtain the corresponding 2a-lower-alkyl-9ahalo-1 l{i-hydroxy-l7,6-acyloxy-4 -androsten-3-one; treating the thus obtained 2a-lower-alkyl-9a-halo-1IB-hydroxy- 17B-acyloxy-4-androsten-3-one in acetone solution with an alkali-metal acetate to obtain the corresponding 2alower allcyl-9/3,1lfi-oxido-l7,8-acyloxy-4-androsten-3-one; treating the thus obtained 2a-lower-alkyl-9-11-oXido-17B- acyloXy-4-androsten-3-one with hydrogen fluoride to obtain the corresponding 2a-lower-alkyl-9a-fluoro-1lfi-hydroxy-l7fi-acyloxy-4-androsten-3-one, oxidizing the thus produced 2a-lower-alkyl-9wfluoro-l 1-;8-hydroXy-17 B-acyloxy-4-androsten-3-one with chromic acid to obtain the corresponding 2a-lower-alkyl-9ix-fiuoro-l7B-acyloxy-4-androstene-3,ll-dione; hydrolyzing the thus obtained 2alower alkyl 9a-fluoro-17fi-acyioXy-4-androstene-3,11-di one with base to give Za-lOWBI-ZllkYl-Qa-flUOIO-l'lfl-hydroxy-4-androstene-3,ll-dione and oxidizing the thus obtainer 2a-lower-alkyl-9a-fluoro-l7 8-hydroxy-4-androstene- 3,1l-dione with chromic acid to obtain 2ot-10wer-alkyl- 9a-fiuoro-4-androstene-3d 1,17-trione.

4. A process for the production of 2ot-methyl-9a-fiuoro- 4-androstene-3,l1,17-trione which comprises: reducing 2a-methyl-11fl-hydroxyi-androstene-3,17-dione with an alkali-metal borohydride and oxidizing the resulting mixture with manganese dioxide to obtain 2a-rnethyl-l1B,17B- dihydroxy-4-androsten-3-one; acylating the thus obtained Za-methyI-I15,l7fi-dihydroxy-4-androsten-3-0ne with acctic anhydride to obtain Za-methyl-llfi-hydroxy-l'm acetoXy-4-androsten-3-one; treating the thus produced 20:- methyl-l'lfi-hydroxy-l75-acet0Xy-4-androsten6-0ne with N-bromoacetamide under anhydrous conditions in an organic base to obtain the corresponding ll-hypohalite and treating the thus obtained ll-hypohalite with anhydrous sulfur dioxide to obtain 2a-methyl-17B-acetoxy-4,9(ll)- androstadien-3-one; treating the thus produced Zea-methyl- 17fi-acetoxy-4,9(l1)-androstadien-3-one with N-bromoacetamide and an aqueous mineral acid to give 2a-rnethyl- 9rx-bI0II10-1lflhydroxy-l7,6-acetoXy4-androsten-3-one; heating the thus produced 2a-methyl-9a-bromo-1lit-hydroxy-17,8-acetoXy-4-androsten-3-one with anhydrous alkali metal acetate to obtain Za-methyI-QBJlfi-oxido-UfiacetoXy-4-androsten-3-one; treating the thus obtained 20:- methyl-9;3,lLB-oxido-l7;?-acetoXy-4-androsten-3-one with hydrogen fluoride to give 2ix-methyl-9u-fluoro-l lfi-hydroxy-l7B-acyloXy-4-androsten-3-one; oxidizing the thus produced 2a-methyl-9 Ot-fiUOI'O-l lfi-hydroxy- 17,6-acetoXy-4- androsten-S-one with chromic acid to obtain Zen-methyl- 9a-fluoro-17B-acetoXy-4-androstene-3,l l-dione; and hydrolyzing the thus produced 2a-Inethyl-9a-fiuor0-l7fl-acetoxy- 4-androstene-3,l1-dione with an alkali metal carbonate to obtain 20: lower-a1kyl-9a-fluoro-17fi-hydroxy-4-androstene-3,l1-dione and oxidizing the thus obtained 20:- methyl fiuoro-l7B-hydroxy-4-androstene-3,1l-dione with chromic acid to obtain 2a-methyl-9a-fluoro-4-androstene-3,11,l7-t1ione.

5. A compound selected from the group consisting of 2a. lower alkyl-9a-halo-17fi-hydroxy-4-androstene-3,1 1- dione and 2OL-IOWBf-filkYl-9Dt-hfll0-17fl-3CY1OXY-4-andl'0- stem-3,1 l-dione wherein the lower-alkyl radical contains from one to eight carbon atoms, inclusive, wherein the acyl group of the acyloxy radical is of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and wherein the halo atom has an atomic weight from 17 to 130, inclusive.

6. 2m-lower alkyl-9 a-halo-4-andr0stene-3,11,17-trione wherein the lower alkyl radical contains from one to eight carbon atoms, inclusive, and wherein the halo atom has an atomic weight from 17 to 130, inclusive.

References Cited in the file of this patent UNITED STATES PATENTS Babcock et a1. Apr. 21, 1959 Wettstein et a1 I an. 21, 1964 OTHER REFERENCES 

3. A PROCESS FOR THE PRODUCTION OF A 2A-LOWER-ALKYL-9AFLUORO-4-ANDROSTEN-3,11,17-TRIONE WHICH COMPRISES THE STEPS: REDUCING A 2A-LOWER-ALKYL-11B-HYDROXY-4-ANDROSTENE-3,17-DIONE WHEREIN THE LOWER-ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, WITH AN ALKALI BOROHYDRIDE TO REDUCE THE 17-KETO GROUP AND OXIDIZING THE RESULTING MIXTURE WITH MANGANESE DIOXIDE TO OBTAIN 2ALOWER-ALKYL-11B, 17B-DIHYDROXY-4-ANDROSTEN-3-ONE; ESTERIFYING THE THUS OBTAINED 2A-LOWER-ALKYL-11B, 17B-DIHYDROXY4-ANDROSTEN-3-ONE WITH AN ACYLATING AGENT SELECTED FROM HALIDES AND ANHYDRIDES OF ORGANIC CARBOXYLIC ACIDS CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, TO OBTAIN THE CORRESPONDING 2A-LOWER-ALKYL-11B-HYDROXY-1(A-ACYLOXY-4-ANDROSTEN-3-ONE; TREATING THE THUS PRODUCED 2ALOWER - ALKYL-ZUUB-HYDROXY-17A-ACYLOXY/4-ANDROSTEN-3-ONE WITH AN N-HALO-ACYLAMIDE WHEREIN THE HALOGEN IS OF ATOMIC WEIGHT 34 TO 130, INCLUSIVE, IN AN ORGANIC BASE UNDER ANHYDROUS CONDITIONS AND TREATING THE THUS PRODUCED INTERMEDIATE, 11B-HYPOHALITE, WITH SULFUR DIOXIDE UNDER ANHYDROUS CONDITIONS TO OBTAIN THE CORRESPONDING 2ALOWER-ALKYL-17B-ACYLOXY-4,9(11)-ANDROSTADIEN-3-ONE; TREATING THE THUS PRODUCED 2A-LOWER-ALKYL-17B-ACYLOXY4,9(11)-ANDROSTADIEN-3-ONE WITH A HYPOHALOUS ACID WHEREIN THE HALOGEN IS OF ATOMIC WEIGHT FROM 33 TO 130, INCLUSIVE, TO OBTAIN THE CORRESPONDING 2A-LOWER-ALKYL-9AHALO-11B-HYDROXY-17B-ACYLOCY-4-ANDROSTEN-O-ONE; TREATING THE THUS OBTAINED 2A-LOWER-ALKYL-9A-HALO-11B-HYDROXY17B-ACYLOXY-4-ANDROSTEN-3-ONE IN ACETONE SOLUTION WITH AN ALKALI-METAL ACETATE TO OBTAIN THE CORRESPONDING 2ALOWER-ALKYL-9B,11B-OXIDO-17B-ACYLOXY-4-ANDROSTEN-3-ONE; TREATING THE THUS OBTAINED 2A-LOWER-ALKYL-9-11-OXIDO-17BACYLOXY-4-ANDROSTEN-3-ONE WITH HYDROGEN FLUORIDE TO OBTAIN THE CORRESPONDING 2A-LOWER-ALKYL-9A-FLUORA-11B-HYDROXY-17B-ACYLOXY-4-ANDROSTEN-3-ONE, OXIDIZING THE THUS PRODUCED 2A-LOWER-ALKYL-9A-FLUORO-11-B-HYDROXY-17B-ACYLOXY-4-ANDROSTEN-3-ONE WITH CHROMIC ACID TO OBTAIN THE CORRESPONDING 2A-LOWER ALKYL-9A-FLUORO-17B-ACYLOXY-4-ANDROSTENE-3,11-DIONE; HYDROLYZING THE THUS OBTAINED 2ALOWER-ALKYL-9A-FLUORO-17B-ACYLOXY-4-ANDROSTENE-3,11-DIONE WITH BASE TO GIVE 2A-LOWER-ALKYL-9A-FLUORO-17B-HYDROXY-4-ANDROSTENE-3,11-DIONE AND OXIDIZING THE THUS OBTAINER 2A-LOWER-ALKYL-9A-FLUORO-17B-HYDROXY-4-ANDROSTENE3,11-DIONE WITH CHROMIC ACID TO OBTAIN 2A-LOWER-ALKYL9A-FLUORO-4-ANDROSTENE-3,11,17-TRIONE.
 6. 2A-LOWER-ALKYL-9A-HALO-4-ANDROSTENE-3,11,17-TRIONE WHEREIN THE LOWER ALKYL RADICAL CONTAINS FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE, AND WHREIN THE HALO ATOMS HAS AN ATOMIC WEIGHT FROM 17 TO 130, INCLUSIVE. 